Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines

Our plain-English summary of Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines, by Y. Wang, A.K. Rishi, V.T. Puliyappadamba, et al (Cancer Chemotherapy and Pharmacology, 2010).

The study

• Authors: Y. Wang, A.K. Rishi, V.T. Puliyappadamba, S. Sharma, H. Yang, A. Tarca, Q.P. Dou, F. Lonardo, J.C. Ruckdeschel, H.I. Pass, A. Wali
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2010;66(3):455-66
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies.

Purpose: To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent.

Methods: Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines.

Results: Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins.

Conclusions: Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.

In plain English

This was a laboratory study of cancer cells grown in culture. It did not study patients or asbestos exposure. The authors tested the drug Velcade (bortezomib) on five cell lines derived from patients with malignant pleural mesothelioma, which were established in their laboratory, and on two breast cancer cell lines. Velcade reduced cell growth in a dose-dependent manner. The dose that halved growth (IC50) was about 40 nM for the mesothelioma cells and 10 to 20 nM for the breast cancer cells. In the mesothelioma lines H2373 and H2595, Velcade caused cells to build up in the G2-M phase of the cell cycle. It also produced markers of programmed cell death (apoptosis). In SKBR-3 breast cancer cells, apoptosis rose three- to fourfold. Four mesothelioma lines were relatively resistant to the chemotherapy drug cisplatin alone, and Velcade pretreatment consistently enhanced cisplatin's growth-inhibiting effect. Velcade also increased the CARP-1, XAF1 and Troy proteins. The authors concluded that Velcade suppresses mesothelioma and breast cancer cell growth partly by activating these apoptosis signals, and they called this a pilot study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of cancer cell lines, using growth assays, flow cytometry, western blotting and gene-expression arrays
• Who was studied: Five malignant pleural mesothelioma cell lines derived from patients and established in the authors' laboratory (H2373, H2452, H2595, H2461, H2714), and two human breast cancer cell lines (MDA-MB-468 and SKBR-3) obtained from ATCC
• Exposure: The proteasome inhibitor Velcade (bortezomib), alone at various doses for 48 h and as a 24 h pretreatment (10 to 40 nM) before 20, 40 or 80 µM cisplatin; asbestos exposure was not studied
• Main results:
  • Velcade inhibited growth of both the mesothelioma and the breast cancer cells in a dose-dependent manner
  • The IC50 (dose halving growth) was about 40 nM for mesothelioma cells and 10 to 20 nM for breast cancer cells
  • In H2373 and H2595 mesothelioma cells, Velcade caused a concentration-dependent G2-M cell cycle arrest
  • In H2373 mesothelioma cells and SKBR-3 breast cancer cells, Velcade caused PARP cleavage, caspase 3 activation and raised Bax expression, in a dose-dependent manner
  • In SKBR-3 breast cancer cells, a DNA fragmentation assay showed a three- to fourfold increase in apoptosis with various Velcade doses
  • Four mesothelioma cell lines were relatively resistant to cisplatin alone, with IC50 values around 80 µM
  • Velcade pretreatment consistently enhanced the growth-inhibitory activity of cisplatin in all the mesothelioma cells tested
  • Velcade increased expression of the CARP-1 protein in mesothelioma and breast cancer cells
  • Velcade increased expression of the XAF1 and Troy proteins in breast cancer and mesothelioma cells
• The authors' conclusion: The authors concluded that Velcade targets cell cycle and apoptosis signaling to suppress mesothelioma and breast cancer cell growth, in part by activating novel transducers of apoptosis. They described the work as a pilot study pointing to further analysis.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelioma, Pleural Mesothelioma, Pleura, Synergistic Effect, Cisplatin.

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